title: Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice.
abstract: Urokinase-type plasminogen activator (uPA) is expressed at elevated levels in atherosclerotic human arteries, primarily in macrophages. Plasminogen (Plg), the primary physiologic substrate of uPA, is present at significant levels in blood and interstitial fluid. Both uPA and Plg have activities that could affect atherosclerosis progression. Moreover, correlations between increased Plg activation and accelerated atherosclerosis are reported in several human studies. However, a coherent picture of the role of the uPA/Plg system in atherogenesis has not yet emerged, with at least one animal study suggesting that Plg is atheroprotective. We used a transgenic mouse model of macrophage-targeted uPA overexpression in apolipoprotein E-deficient mice to investigate the roles of uPA and Plg in atherosclerosis. We found that macrophage-expressed uPA accelerated atherosclerotic plaque growth and promoted aortic root dilation through Plg-dependent pathways. These pathways appeared to affect lesion progression rather than initiation and to include actions that disproportionately increase lipid accumulation in the artery wall. In addition, loss of Plg was protective against atherosclerosis both in the presence and absence of uPA overexpression. Transgenic mice with macrophage-targeted uPA overexpression reveal atherogenic roles for both uPA and Plg and are a useful experimental setting for investigating the molecular mechanisms that underlie clinically established relationships between uPA expression, Plg activation, and atherosclerosis progression.
authors.affiliation: Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Seattle, WA 98195, USA.
authors.forename: Michal
authors.initials: M
authors.lastname: Kremen
authors.forename: Ranjini
authors.initials: R
authors.lastname: Krishnan
authors.forename: Isaac
authors.initials: I
authors.lastname: Emery
authors.forename: Jie Hong
authors.initials: JH
authors.lastname: Hu
authors.forename: Katherine I
authors.initials: KI
authors.lastname: Slezicki
authors.forename: Alyssa
authors.initials: A
authors.lastname: Wu
authors.forename: Kun
authors.initials: K
authors.lastname: Qian
authors.forename: Liang
authors.initials: L
authors.lastname: Du
authors.forename: Abigail
authors.initials: A
authors.lastname: Plawman
authors.forename: April
authors.initials: A
authors.lastname: Stempien-Otero
authors.forename: David A
authors.initials: DA
authors.lastname: Dichek
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D023921:Coronary Stenosis / Q000473:pathology; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010958:Plasminogen / Q000378:metabolism*; D019076:Transgenes; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D010958:Plasminogen; D014568:Urokinase-Type Plasminogen Activator